Ashwin Ashok Kumar Sreelatha

University of Tübingen

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Manu Sharma

University of Tübingen

Rejko Krüger

Luxembourg Institute of Health

Thomas Gasser

Hertie Institute for Clinical Brain Research

Patrick May

University of Luxembourg

Lasse Pihlstrøm

Oslo University Hospital

Cornelis Blauwendraat

National Institutes of Health

Mathias Toft

Oslo University Hospital

Claudia Schulte

Hertie Institute for Clinical Brain Research

Peter Lichtner

Helmholtz Zentrum München

Dheeraj Reddy Bobbili

University of Luxembourg

Cooperative Institutions

Inserm

111

Centre de recherche en Epidémiologie et Santé des Populations

Université de Versailles Saint-Quentin-en-Yvelines

Université Paris-Saclay

Center for Human Genetics

Hertie Institute for Clinical Brain Research

University of Tübingen

Oslo University Hospital

National Institutes of Health

National Institute on Aging

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Fine mapping of the HLA locus in Parkinson’s disease in Europeans

medRxiv (Cold Spring Harbor Laboratory) (2020)

Eric Yu Aditya Ambati Maren Stolp Andersen Lynne Krohn Mehrdad A. Estiar

Abstract Objective To fine map the association between human leukocyte antigen ( HLA) genes and Parkinson’s disease (PD) that was discovered using genome-wide association studies (GWASs). Methods We performed a thorough analysis of the HLA locus in 13,770 PD patients, 20,214 proxy-cases and 490,861 controls of European origin. We used GWAS data to impute HLA types and performed multiple regression models to examine the association of specific HLA types, different haplotypes and specific amino acid changes. We further performed conditional analyzes to identify specific alleles or genetic variants that drive the association with PD. Results Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1 *03:01, HLA-DQB1 *03:02, HLA-DRB1 *04:01 and HLA-DRB1 *04:04. Haplotype analyzes followed by amino-acid analysis and conditional analyzes suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1 *04 subtypes - 11V, 13H and 33H (OR=0.87 95%CI=0.83-0.90, p <8.23×10 −9 for all three variants). No other effects were present after adjustment for these amino acids. Conclusions Our results suggest that specific variants in the HLA-DRB1 gene are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to identification of new targets for therapeutics development.

Genome-wide Association Study

Genetic Association

10.1101/2020.10.29.20217059

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Genome-wide association study of copy number variations in Parkinson's disease

medRxiv (Cold Spring Harbor Laboratory) (2024)

Zied Landoulsi Ashwin Ashok Kumar Sreelatha Claudia Schulte Dheeraj Reddy Bobbili Ludovica Montanucci

Our study investigates the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data, aiming to uncover novel genetic mechanisms and improve the understanding of the role of CNVs in sporadic PD.

Genome-wide Association Study

Genetic Association

Pathogenesis

10.1101/2024.08.21.24311915

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Deciphering the Genetic Architecture of Parkinsons Disease in India

medRxiv (Cold Spring Harbor Laboratory) (2025)

Asha Kishore Ashwin Ashok Kumar Sreelatha Amabel Tenghe Rupam Borgohain Divya Kalikavil Puthanveedu

The genomic landscape of the Indian population, particularly for age-related disorders like Parkinsons disease (PD) remains underrepresented in global research. Genetic variability in PD has been studied predominantly in European populations, offering limited insights into its role within the Indian population. To address this gap, we conducted the first pan-India genomic survey of PD involving 4,806 cases and 6,364 controls, complemented by a meta-analysis integrating summary statistics from a multi-ancestry PD meta-analysis (N=611,485). We further leveraged RNA-sequencing data from lymphoblastoid cell lines of 731 individuals from the 1000 Genomes project to evaluate the expression of key loci across global populations. Our findings reveal a higher genetic burden of PD in the Indian population compared to Europeans, accounting for ~30% of the previously unexplained heritability. Thirteen genome-wide significant loci were identified, including two novel loci, with an additional three loci uncovered through meta-analysis. Polygenic risk score analysis showed moderate transferability from European populations. Our results highlight the importance of genetic loci in immune function, lipid metabolism and SNCA aggregation in PD pathogenesis, with gene expression variability emphasizing population-specific differences. We also established South Asias largest PD biobank, providing a foundation for patient-centric approaches to PD research and treatment in India.

Genetic architecture

10.1101/2025.02.17.25322132

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Resequencing the complete SNCA locus in Indian patients with Parkinson’s disease

npj Parkinson s Disease (2024)

Asha Kishore Marc Sturm Kanchana Soman Pillai Christopher Hakkaart Divya Kalikavil Puthanveedu

Abstract The genetic loci implicated in familial Parkinson’s disease (PD) have limited generalizability to the Indian PD population. We tested mutations and the frequency of known mutations in the SNCA gene in a PD cohort from India. We selected 298 PD cases and 301 age-matched controls for targeted resequencing (before QC), along with 363 PD genomes of Indian ancestry and 1029 publicly available whole genomes from India as healthy controls (IndiGenomes), to determine the frequency of monogenic SNCA mutations. The raw sequence reads were analyzed using an in-house analysis pipeline, allowing the detection of small variants and structural variants using Manta. The in-depth analysis of the SNCA locus did not identify missense or structural variants, including previously identified SNCA mutations, in the Indian population. The familial forms of SNCA gene variants do not play a major role in the Indian PD population and this warrants further research in the under-represented population.

10.1038/s41531-024-00676-4

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GenoTools: An Open-Source Python Package for Efficient Genotype Data Quality Control and Analysis

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Dan Vitale Mathew J. Koretsky Nicole Kuznetsov Samantha Hong Jessica Martin

GenoTools, a Python package, streamlines population genetics research by integrating ancestry estimation, quality control (QC), and genome-wide association studies (GWAS) capabilities into efficient pipelines. By tracking samples, variants, and quality-specific measures throughout fully customizable pipelines, users can easily manage genetics data for large and small studies. GenoTools' "Ancestry" module renders highly accurate predictions, allowing for high-quality ancestry-specific studies, and enables custom ancestry model training and serialization, specified to the user's genotyping or sequencing platform. As the genotype processing engine that powers several large initiatives, including the NIH's Center for Alzheimer's and Related Dementias (CARD) and the Global Parkinson's Genetics Program (GP2). GenoTools was used to process and analyze the UK Biobank and major Alzheimer's Disease (AD) and Parkinson's Disease (PD) datasets with over 400,000 genotypes from arrays and 5000 sequences and has led to novel discoveries in diverse populations. It has provided replicable ancestry predictions, implemented rigorous QC, and conducted genetic ancestry-specific GWAS to identify systematic errors or biases through a single command. GenoTools is a customizable tool that enables users to efficiently analyze and scale genotype data with reproducible and scalable ancestry, QC, and GWAS pipelines.

Python

Genome-wide Association Study

Population stratification

R package

Genetic Association

10.1101/2024.03.26.586362

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Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson's disease

Zenodo (CERN European Organization for Nuclear Research) (2023)

Giuseppe Arena Zied Landoulsi Dajana Großmann Armelle Vitali Sylvie Delcambre

Background Parkinson’s disease (PD) is the fastest growing neurodegenerative disorder, with affected individuals expected to double during the next 20 years. This raises the urgent need to better understand the genetic architecture and downstream cellular alterations underlying PD pathogenesis, in order to identify more focused therapeutic targets. While only ∼10% of PD cases can be clearly attributed to monogenic causes, there is mounting evidence that additional genetic factors could play a role in idiopathic PD (iPD). In particular, common variants with low to moderate effect size in multiple genes regulating key neuroprotective activities may act as risk factors for PD. In light of the well-established involvement of mitochondrial dysfunction in PD, we hypothesized that a fraction of iPD cases may harbour a pathogenic combination of common variants in nuclear-encoded mitochondrial genes, ultimately resulting in neurodegeneration. Methods to capture this mitochondria-related “missing heritability”, we leveraged on existing data from previous genome-wide association studies (GWAS) – i.e., the large PD GWAS from Nalls and colleagues. We then used computational approaches based on mitochondria-specific polygenic risk scores (mitoPRSs) for imputing the genotype data obtained from different iPD case-control datasets worldwide, including the Luxembourg Parkinson’s Study (412 iPD patients and 576 healthy controls) and the COURAGE-PD cohorts (7270 iPD cases and 6819 healthy controls). Results applying this approach to gene sets controlling mitochondrial pathways potentially relevant for neurodegeneration in PD, we demonstrated that common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk both in the Luxembourg Parkinson’s Study (odds ratio, OR=1.31[1.14-1.50], p=5.4e-04) and in COURAGE-PD (OR=1.23[1.18-1.27], p=1.5e-29). Functional analyses in primary skin fibroblasts and in the corresponding induced pluripotent stem cells-derived neuronal progenitor cells from Luxembourg Parkinson’s Study iPD patients stratified according to the OXPHOS-PRS, revealed significant differences in mitochondrial respiration between high and low risk groups (p < 0.05). Finally, we also demonstrated that iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients. Conclusions our findings suggest that OXPHOS-PRS may represent a promising strategy to stratify iPD patients into pathogenic subgroups – in which the underlying neurodegeneration is due to a genetically defined mitochondrial burden – potentially eligible for future, more tailored mitochondrially targeted treatments.

Polygenic risk score

10.5281/zenodo.7973685

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Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson’s disease

medRxiv (Cold Spring Harbor Laboratory) (2023)

Giuseppe Arena Zied Landoulsi Dajana Großmann Armelle Vitali Sylvie Delcambre

Abstract Background Parkinson’s disease (PD) is the fastest growing neurodegenerative disorder, with affected individuals expected to double during the next 20 years. This raises the urgent need to better understand the genetic architecture and downstream cellular alterations underlying PD pathogenesis, in order to identify more focused therapeutic targets. While only ∼10% of PD cases can be clearly attributed to monogenic causes, there is mounting evidence that additional genetic factors could play a role in idiopathic PD (iPD). In particular, common variants with low to moderate effect size in multiple genes regulating key neuroprotective activities may act as risk factors for PD. In light of the well-established involvement of mitochondrial dysfunction in PD, we hypothesized that a fraction of iPD cases may harbour a pathogenic combination of common variants in nuclear-encoded mitochondrial genes, ultimately resulting in neurodegeneration. Methods to capture this mitochondria-related “missing heritability”, we leveraged on existing data from previous genome-wide association studies (GWAS) – i.e., the large PD GWAS from Nalls and colleagues. We then used computational approaches based on mitochondria-specific polygenic risk scores (mitoPRSs) for imputing the genotype data obtained from different iPD case-control datasets worldwide, including the Luxembourg Parkinson’s Study (412 iPD patients and 576 healthy controls) and the COURAGE-PD cohorts (7270 iPD cases and 6819 healthy controls). Results applying this approach to gene sets controlling mitochondrial pathways potentially relevant for neurodegeneration in PD, we demonstrated that common variants in genes regulating Oxidative Phosphorylation (OXPHOS -PRS ) were significantly associated with a higher PD risk both in the Luxembourg Parkinson’s Study (odds ratio, OR=1.31[1.14-1.50], p =5.4e-04) and in COURAGE-PD (OR=1.23[1.18-1.27], p =1.5e-29). Functional analyses in primary skin fibroblasts and in the corresponding induced pluripotent stem cells-derived neuronal progenitor cells from Luxembourg Parkinson’s Study iPD patients stratified according to the OXPHOS -PRS, revealed significant differences in mitochondrial respiration between high and low risk groups ( p < 0.05). Finally, we also demonstrated that iPD patients with high OXPHOS -PRS have a significantly earlier age at disease onset compared to low-risk patients. Conclusions our findings suggest that OXPHOS-PRS may represent a promising strategy to stratify iPD patients into pathogenic subgroups – in which the underlying neurodegeneration is due to a genetically defined mitochondrial burden – potentially eligible for future, more tailored mitochondrially targeted treatments.

Genome-wide Association Study

Genetic Association

Mitochondrial disease

10.1101/2023.05.12.23289877

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Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Movement Disorders (2022)

Cloé Domenighetti Pierre‐Emmanuel Sugier Ashwin Ashok Kumar Sreelatha Claudia Schulte Sandeep Grover

Abstract Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two‐sample Mendelian randomization (MR). Methods We genotyped a well‐established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage‐PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P ‐difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

Mendelian Randomization

10.1002/mds.28902

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A Novel PINK1 p.F385S Loss‐of‐Function Mutation in an Indian Family with Parkinson's Disease

Movement Disorders (2024)

Karan Sharma Asha Kishore Anna Lechado‐Terradas Raffaele Passannanti Francesco Raimondi

Abstract Background Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. Objective The aim of this study was to characterize a novel phosphatase tensin homolog‐induced serine/threonine kinase 1 ( PINK1 ) mutation causing PD in an Indian family. Methods Exome sequencing of a well‐characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. Results We identified a homozygous chr1:20648535–20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1 , which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved DFG motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. Conclusions We characterized a novel nonconservative mutation in the DFG motif of PINK1 , which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PINK1

LRRK2

10.1002/mds.29792

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Clinical and Epidemiological Profile of Parkinson's Disease in India

Asha Kishore Rupam Borgohain Divya Kalikavil Puthenveedu Roopa Rajan Pramod Kumar Pal

10.2139/ssrn.5076144

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